Alkene derivatives as sphingosine 1-phosphate (S1P) receptor modulators

ABSTRACT

The present invention relates to novel alkene derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/419,276 filed Dec. 3, 2010, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel pyridine derivatives, processesfor preparing them, pharmaceutical compositions containing them andtheir use as pharmaceuticals, as modulators of sphingosine-1-phosphatereceptors. The invention relates specifically to the use of thesecompounds and their pharmaceutical compositions to treat disordersassociated with sphingosine-1-phosphate (S1P) receptor modulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

A group of novel alkene derivatives which are potent and selectivesphingosine-1-phosphate modulators has been discovered. As such, thecompounds described herein are useful in treating a wide variety ofdisorders associated with modulation of sphingosine-1-phosphatereceptors. The term “modulator” as used herein, includes but is notlimited to: receptor agonist, antagonist, inverse agonist, inverseantagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:

-   A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;-   B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;-   R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂,    NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂,    NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂,    NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or    hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or    hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or    hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or    hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or    hydroxyl;-   R¹¹ is H or C₁₋₈ alkyl;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl;-   R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and-   R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound having FormulaI wherein:

-   A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;    and-   B is C₆₋₁₀ aryl.

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

-   R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁵ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁶ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁸ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂,-   R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and-   R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound having FormulaI wherein:

-   R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁴ is H, halogen or C₁₋₆ alkyl;-   R⁵ is H, halogen or C₁₋₆ alkyl;-   R⁶ is H, halogen or C₁₋₆ alkyl;-   R⁷ is H, halogen or C₁₋₆ alkyl;-   R⁸ is H, halogen or C₁₋₆ alkyl;-   R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and-   R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound having FormulaI wherein:

-   R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂;-   R⁴ is H, halogen or C₁₋₆ alkyl;-   R⁵ is H, halogen or C₁₋₆ alkyl;-   R⁶ is H, halogen or C₁₋₆ alkyl;-   R⁷ is H;-   R⁸ is H;-   R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and-   R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₈cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl,cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid,phosphonic acid groups, sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by C₁₋₈ alkyl groups or halogens.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be substituted by C₁₋₈ alkylgroups or halogens.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₈ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. Heterocycle can be monocyclic or polycyclic. The heterocyclicring can be interrupted by a C═O; the S heteroatom can be oxidized.Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moietiescan be substituted by hydroxyl, C₁₋₈ alkyl or halogens.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic.Aryl can be substituted by halogen atoms, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN,—C(O)H or —C(O)(C₁₋₆ alkyl), NH(C₁₋₆ alkyl), NH₂, N(C₁₋₆ alkyl) (C₁₋₆alkyl), NO₂ or hydroxyl. Usually aryl is phenyl.

-   -   The term “hydroxyl” as used herein, represents a group of        formula “—OH”.    -   The term “carbonyl” as used herein, represents a group of        formula “—C(O)”.    -   The term “carboxyl” as used herein, represents a group of        formula “—C(O)O—”.    -   The term “sulfonyl” as used herein, represents a group of        formula “—SO₂”.    -   The term “sulfate” as used herein, represents a group of formula        “—O—S(O)₂—O—”.    -   The term “carboxylic acid” as used herein, represents a group of        formula “—C(O)ON”.    -   The term “sulfoxide” as used herein, represents a group of        formula “—S═O”.    -   The term “phosphonic acid” as used herein, represents a group of        formula “—P(O)(OH)₂”.

-   The term “phosphoric acid” as used herein, represents a group of    formula “—(O)P(O)(OH)₂”.    -   The term “sulphonic acid” as used herein, represents a group of        formula “—S(O)₂OH”.    -   The formula “H”, as used herein, represents a hydrogen atom.    -   The formula “O”, as used herein, represents an oxygen atom.    -   The formula “N”, as used herein, represents a nitrogen atom.    -   The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   3-{5-[(E)-2-(3,4-dimethoxyphenyl)-1-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(4-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-dichlorophenyl)-1-phenylvinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-fluorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(Z)-2-(3,4-dimethylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   N-Methyl-3-{5-[(Z)-2-(4-methylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}pyridin-2-amine;-   3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-(trifluoromethyl)phenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-[(E)-2-(3,4-Dimethylphenyl)-1-{3-[2-(methylamino)pyridin-3-yl]-1,2,4-oxadiazol-5-yl]vinyl}benzonitrile;-   3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-nitrophenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(3,5-Difluorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(2-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(1-naphthyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(3-Chlorophenyl)-2-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(3-Chlorophenyl)-2-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(3-Chlorophenyl)-2-(2-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(4-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[(E)-1-(2-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts,P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica ChemicaActa-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation.

-   -   Therapeutic utilities of S1P modulators are Ocular Diseases: wet        and dry age-related macular degeneration, diabetic retinopathy,        retinopathy of prematurity, retinal edema, geographic atrophy,        glaucomatous optic neuropathy, chorioretinopathy, hypertensive        retinopathy, ocular ischemic syndrome, prevention of        inflammation-induced fibrosis in the back of the eye, various        ocular inflammatory diseases including uveitis, scleritis,        keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immnuosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries; Organ transplants: renal, corneal, cardiac and adipose        tissue transplants.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of Ocular Diseases: wet and dry age-relatedmacular degeneration, diabetic retinopathy, retinopathy of prematurity,retinal edema, geographic atrophy, glaucomatous optic neuropathy,chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome,prevention of inflammation-induced fibrosis in the back of the eye,various ocular inflammatory diseases including uveitis, scleritis,keratitis, and retinal vasculitis;

-   Systemic vascular barrier related diseases: various inflammatory    diseases, including acute lung injury, its prevention, sepsis, tumor    metastasis, atherosclerosis, pulmonary edemas, and    ventilation-induced lung injury;-   Autoimmune diseases and immnuosuppression: rheumatoid arthritis,    Crohn's disease, Graves' disease, inflammatory bowel disease,    multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative    colitis, antoimmune uveitis, renal ischemia/perfusion injury,    contact hypersensitivity, atopic dermititis, and organ    transplantation;-   Allergies and other inflammatory diseases: urticaria, bronchial    asthma, and other airway inflammations including pulmonary emphysema    and chronic obstructive pulmonary diseases;-   Cardiac functions: bradycardia, congestional heart failure, cardiac    arrhythmia, prevention and treatment of atherosclerosis, and    ischemia/reperfusion injury;-   Wound Healing: scar-free healing of wounds from cosmetic skin    surgery, ocular surgery, GI surgery, general surgery, oral injuries,    various mechanical, heat and burn injuries, prevention and treatment    of photoaging and skin ageing, and prevention of radiation-induced    injuries;-   Bone formation: treatment of osteoporosis and various bone fractures    including hip and ankles;-   Anti-nociceptive activity: visceral pain, pain associated with    diabetic neuropathy, rheumatoid arthritis, chronic knee and joint    pain, tendonitis, osteoarthritis, neuropathic pains;-   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,    proliferative vitreoretinopathy, cicatricial pemphigoid, surgically    induced fibrosis in cornea, conjunctiva and tenon;-   Pains and anti-inflammation: acute pain, flare-up of chronic pain,    musculo-skeletal pains, visceral pain, pain associated with diabetic    neuropathy, rheumatoid arthritis, chronic knee and joint pain,    tendonitis, osteoarthritis, bursitis, neuropathic pains;-   CNS neuronal injuries: Alzheimer's disease, age-related neuronal    injuries;-   Organ transplants: renal, corneal, cardiac and adipose tissue    transplants.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I.

The following abbreviations are used in the general scheme and in thespecific examples:

CDI 1,1′-carbonyl diimidazole EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide NBS N-bromosuccinimide BPO benzoyl peroxide KOH potassiumhydroxide MeOH methanol HCl hydrochloric acid rt room temperature CDCl₃deuterated chloroform DMSO-d₆ deuterated dimethyl sulfoxide Ac₂O aceticanhydride

Intermediate (E)-2-(substituted aryl)-3-(substituted aryl)acrylic acidwas obtained from the appropriately substituted arylacetic acid (1 eq),the appropriately substituted arylaldehyde (1 eq), acetic anhydride (2.5eq) and potassium carbonate (5.0 eq) according to the synthetic protocolpublished in Brison, Jean et al. Bulletin des Societes Chimiques Beiges,1983, vol. 92, (10) p. 893-900.

This acrylic acid (1 to 10 mmol) was then dissolved in 50 ml ofdichloroethane at room temperature. CDI or EDCI (1.5 eq) was added andthe resulting reaction mixture was stirred for 10 minutes. The(Z)—N′-Hydroxy-2-(methylamino)nicotinimidamide derivative (1.5 eq) wasadded, and the resulting reaction mixture was stirred at roomtemperature for 2 hours, then heated at 95° C. and stirred for 14 hours.The reaction mixture was cooled to room temperature, concentrated anddiluted with ethyl acetate. The organic phase was washed sequentiallywith water and brine, then dried with sodium sulfate and concentrated.Flash chromatography (30% EtOAc/hexanes) gave the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hyrdrogen ¹H (orH) or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8, intermediates' andreagents' names used in the examples were generated with software suchas Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw2.5 SP1.

In general, characterization of the compounds is performed using NMRspectra, which were recorded on 300 and/or 600 MHz Varian and acquiredat room temperature. Chemical shifts are given in ppm referenced eitherto internal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

The following synthetic schemes illustrate how compounds according tothe invention can be made. Those skilled in the art will be routinelyable to modify and/or adapt the following schemes to synthesize anycompound of the invention covered by Formula I.

Compounds 1 through 8 were prepared according to the general proceduredescribed above. The diphenylacrylic acid intermediate, obtained fromthe corresponding arylacetic acid and the corresponding aldehydederivative, was treated with(Z)—N′-Hydroxy-2-(methylamino)nicotinimidamide (CAS 801303-19-5). Thestarting materials for obtaining the diphenylacrylic acid component andthe results are tabulated below in Table 1.

TABLE 1 Staring ¹H NMR δ (ppm) for Comp. No. IUPAC name materialsCompound 1 3-{5-[(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)dimethoxyphenyl)-1-(4- acid, 4-methyl- δ ppm 2.39 (s, 3 H) 3.03 (d,methylphenyl)vinyl]- (CAS 622-47-9) J = 4.69 Hz, 3 H) 3.38 (s, 3 H)1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 3.74 (s, 3 H) 6.64 (d, J = 2.05methylpyridin-2-amine 3,4-dimethoxy- Hz, 1 H) 6.73 (dd, J = 7.62,

(CAS 120-14-9) 4.69 Hz, 1 H) 6.87-6.99 (m, 2 H) 7.08 (d, J = 4.69 Hz, 1N—H) 7.27-7.38 (m, 4 H) 8.01 (s, 1 H) 8.18 (dd, J = 7.62, 1.76 Hz, 1 H)8.28 (dd, J = 4.83, 1.90 Hz, 1 H). 2 3-{5-[(E)-2-(3,4- Benzeneacetic ¹HNMR (300 MHz, DMSO-d₆) dimethylphenyl)-1-(4- acid, 4-methoxy δ ppm 2.10(s, 3 H) 2.18 (s, 3 methoxyphenyl)vinyl]- (CAS 104-01-8) H) 3.03 (d, J =4.69 Hz, 3 H) 1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 3.83 (s, 3 H) 6.73(dd, J = 7.62, methylpyridin-2-amine 3,4-dimethyl- 4.98 Hz, 1 H) 6.88(d, J = 7.91

(CAS 5973-71-7) Hz, 1 H) 6.99-7.12 (m, 5 H) 7.27-7.33 (m, 2 H) 7.97 (s,1 H) 8.19 (dd, J = 7.47, 1.90 Hz, 1 H) 8.29 (dd, J = 4.83, 1.90 Hz, 1H). 3 3-{5-[(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)dichlorophenyl)-1- acid δ ppm 3.03 (d, J = 4.69 Hz, 3phenylvinyl]-1,2,4- (CAS 103-82-2) H) 6.74 (dd, J = 7.62, 4.69 Hz,oxadiazol-3-yl}-N- Benzaldehyde, 1 H) 7.08 (d, J = 4.69 Hz, 1 N—methylpyridin-2-amine 3,4-dichloro- H) 7.14 (dd, J = 8.64, 1.90 Hz,

(CAS 6287-38-3) 1 H) 7.38-7.46 (m, 3 H) 7.49- 7.58 (m, 4 H) 8.10 (s, 1H) 8.17 (dd, J = 7.62, 2.05 Hz, 1 H) 8.29 (dd, J = 4.84, 1.90 Hz, 1 H).4 3-{5-[(E)-1-(4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)chlorophenyl)-2-(3,4- acid, 4-chloro δ ppm 3.03 (d, J = 4.69 Hz, 3dichlorophenyl)vinyl]- (CAS 1878-66-6) H) 6.74 (dd, J = 7.62, 4.98 Hz,1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 1 H) 7.07 (d, J = 4.69 Hz, 1N—methylpyridin-2-amine 3,4-dichloro- H) 7.09-7.13 (m, 1 H) 7.43-

(CAS 6287-38-3) 7.49 (m, 2 H) 7.52 (d, J = 2.05 (m, 1 H) 7.55-7.63 (m 3H) 8.12 (s, 1 H) 8.17 (dd, J = 7.62, 1.76 Hz, 1 H) 8.29 (dd, J = 4.84,1.90 Hz, 1 H). 5 3-{5-[(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz, CDCl₃)δ Dimethylphenyl)-1-(3- acid, 3-fluoro- ppm 2.14 (s, 3 H), 2.23 (s, 3fluorophenyl)vinyl]- (CAS 331-25-9) H), 3.14 (d, J = 4.69 Hz, 3 H),1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 6.65 (dd, J = 7.47, 5.13 Hz, 1methylpyridin-2-amine 3,4-dimethyl- H), 6.81-6.89 (m, 1 H), 6.91-

(CAS 5973-71-7) 7.02 (m, 2 H), 7.05-7.22 (m, 4 H), 7.34-7.50 (m, 1 H),7.99 (s, 1 H), 8.23-8.38 (m, 2 H). 6 3-{5-[(E)-2-(3,4- Benzeneacetic ¹HNMR (300 MHz, DMSO-d₆) Dimethylphenyl)-1-(3- acid, 3-methyl- δ ppm 2.06(s, 3 H), 2.15 (s, 3 methylphenyl)vinyl]- (CAS 621-36-3) H), 2.33 (s, 3H), 3.01 (d, 1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, J = 4.69 Hz, 3 H),6.64-6.75 methylpyridin-2-amine 3,4-dimethyl- (m, 1 H), 6.81-6.89 (m, 1H),

(CAS 5973-71-7) 6.94-7.03 (m, 2 H), 7.04- 7.11 (m, 1 H), 7.12-7.17 (m, 1H), 7.18-7.23 (m, 1 H), 7.26-7.33 (m, 1 H), 7.34- 7.43 (m, 1 H), 7.99(s, 1 H), 8.13-8.21 (m, 1 H), 8.24- 8.32 (m, 1 H). 7 3-{5-[(E)-1-(3-Benzeneacetic ¹H NMR (300 MHz, CDCl₃) δ Chlorophenyl)-2-(3,4- acid,3-chloro- ppm 2.15 (s, 3 H), 2.23 (s, 3 dimethylphenyl)vinyl]- (CAS1878-65-5) H), 3.15 (d, J = 4.69 Hz, 3 H), 1,2,4-oxadiazol-3-yl}-N-Benzaldehyde, 6.66 (dd, J = 7.33, 4.98 Hz, 1 methylpyridin-2-amine3,4-dimethyl- H), 6.79-6.90 (m, 1 H), 6.93-

(CAS 5973-71-7) 7.02 (m, 2 H), 7.06-7.21 (m, 1 H), 7.23-7.31 (m, 1 H),7.35-7.50 (m, 3 H), 7.99 (s, 1 H), 8.23-8.42 (m, 2 H). 83-{5-[(E)-2-(3,4- 3- ¹H NMR (300 MHz, DMSO-d₆) Dimethylphenyl)-1-(3-Thiopheneacetic δ ppm 2.07 (s, 3 H), 2.16 (s, 3 thienyl)vinyl]-1,2,4-acid H), 3.01 (d, J = 4.69 Hz, 3 H), oxadiazol-3-yl}-N- (CAS 6964-21-2)6.71 (dd, J = 7.62, 4.69 Hz, 1 methylpyridin-2-amine Benzaldehyde, H),6.85-6.96 (m, 1 H), 6.97-

3,4-dimethyl- (CAS 5973-71-7) 7.15 (m, 4 H), 7.56-7.74 (m, 2 H), 7.96(s, 1 H), 8.18 (dd, J = 7.62, 1.76 Hz, 1 H), 8.26 (dd, J = 4.83, 1.90Hz, 1 H). 9 3-{5-[(Z)-2-(3,4- 2- ¹H NMR (300 MHz, DMSO-d₆)dimethylphenyl)-1-(2- Thiopheneacetic δ ppm 2.09 (s, 3 H), 2.17 (s, 3thienyl)vinyl]-1,2,4- acid H), 3.01 (d, J = 4.69 Hz, 3 H),oxadiazol-3-yl}-N- (CAS 1918-77-0) 6.71 (dd, J = 7.62, 4.69 Hz, 1methylpyridin-2-amine Benzaldehyde, H), 6.93-7.01 (m, 1 H), 7.03-

3,4-dimethyl- (CAS 5973-71-7) 7.11 (m, 3 H), 7.18-7.24 (m, 2 H),7.73-7.79 (m, 1 H), 8.06 (s, 1 H), 8.18 (dd, J = 7.62, 1.76 Hz, 1 H),8.27 (dd, J = 4.69, 1.76 Hz, 1 H). 10 N-Methyl-3-{5-[(Z)-2-(4- 2- ¹H NMR(300 MHz, DMSO-d₆) methylphenyl)-1-(2- Thiopheneacetic δ ppm 2.25 (s, 3H), 3.00 (d, thienyl)vinyl]-1,2,4- acid J = 4.40 Hz, 3 H), 6.70 (dd,oxadiazol-3-yl}pyridin-2- (CAS 1918-77-0) J = 7.62, 4.98 Hz, 1 H), 7.01-amine Benzaldehyde, 7.12 (m, 4 H), 7.14-7.23 (m,

4-methyl- (CAS 104-87-0) 4 H), 7.70-7.78 (m, 1 H), 8.07 (s, 1 H), 8.17(dd, J = 7.62, 1.76 Hz, 1 H), 8.26 (dd, J = 4.83, 1.90 Hz, 1 H). 113-(5-{(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)Dimethylphenyl)-1-[3- acid, 3- δ ppm 2.04 (s, 3 H), 2.15 (s, 3(trifluoromethyl)phenyl] (trifluoromethyl)- H), 3.00 (d, J = 4.69 Hz, 3H), vinyl}-1,2,4-oxadiazol-3- (CAS 351-35-9) 6.70 (dd, J = 7.62, 4.69Hz, 1 yl)-N-methylpyridin-2- Benzaldehyde, H), 6.82 (d, J = 7.91 Hz, 1H), amine 3,4-dimethyl- 6.93 (s, 1 H), 6.98-7.09 (m, 2

(CAS 5973-71-7) H), 7.69-7.76 (m, 2 H), 7.81 (s, 1 H), 7.84-7.89 (m, 1H), 8.06 (s, 1 H), 8.13 (dd, J = 7.62, 2.05 Hz, 1 H), 8.26 (dd, J =4.84, 1.90 Hz, 1 H). 12 3-[(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz,DMSO- Dimethylphenyl)-1-{3-[2- acid, 3-cyano d6) δ ppm 2.07 (s, 3 H),2.16 (methylamino)pyridin-3- (CAS 1878-71-3) (s, 3 H), 3.01 (d, J = 4.69Hz, 3 y1]-1,2,4-oxadiazol-5- Benzaldehyde, H), 6.71 (dd, J = 7.62, 4.98Hz, yl}vinyl]benzonitrile 3,4-dimethyl- 1 H), 6.81 (d, J = 7.91 Hz, 1H),

(CAS 5973-71-7) 6.96-7.12 (m, 3 H), 7.67- 7.77 (m, 2 H), 7.93-7.99 (m, 2H), 8.07 (s, 1 H), 8.14 (dd, J = 7.62, 2.05 Hz, 1 H), 8.27 (dd, J =4.69, 1.76 Hz, 1 H). 13 3-(5-{(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz,DMSO-d₆) Dimethylphenyl)-1-[3- acid, 3-nitro- δ ppm 2.06 (s, 3 H), 2.14(s, 3 nitrophenyl]vinyl}-1,2,4- (CAS 1877-73-2) H), 3.00 (d, J = 4.69Hz, 3 H), oxadiazol-3-y1)-N- Benzaldehyde, 6.69 (dd, J = 7.62, 4.98 Hz,1 methylpyridin-2-amine 3,4-dimethyl- H), 6.81 (dd, J = 7.91, 1.46 Hz,

(CAS 5973-71-7) 1 H), 6.95-7.02 (m, 2 H), 7.05 (d, J = 4.98 Hz, 1 H),7.71- 7.80 (m, 1 H), 7.81-7.87 (m, 1 H), 8.08-8.15 (m, 2 H), 8.25 (dd, J= 4.83, 1.90 Hz, 1 H), 8.31-8.37 (m, 2 H). 14 3-{5-[(E)-1-(3,5-Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆) Difluorophenyl)-2-(3,4- acid,3,5- δ ppm 2.04-2.14 (m, 3 H), dimethylphenyl)vinyl]- difluoro 2.18 (s,3 H), 3.01 (d, J = 4.10 1,2,4-oxadiazol-3-yl}-N- (CAS 105184-38-1) Hz, 3H), 6.73 (d, J = 4.40 Hz, 1 methylpyridin-2-amine Benzaldehyde, H), 6.87(d, J = 8.20 Hz, 1 H),

3,4-dimethyl- (CAS 5973-71-7) 7.06 (d, J = 9.38 Hz, 3 H), 7.21 (d, J =6.15 Hz, 1 H), 7.26- 7.34 (m, 1 H), 7.34-7.46 (m, 1 H), 8.05 (s, 1 H),8.16 (d, J = 7.33 Hz, 1 H), 8.28 (br. s., 1 H). 15 3-{5-[(E)-2-(3,4-Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆) Dimethylphenyl)-1-(3- acid, 3- δppm 2.06 (s, 3 H), 2.15 (s, 3 methoxyphenyl)vinyl]- methoxy- H), 3.01(d, J = 4.69 Hz, 3 H), 1,2,4-oxadiazol-3-yl}-N- (CAS 1798-09-0) 3.73 (s,3 H), 6.71 (dd, methylpyridin-2-amine Benzaldehyde, J = 7.47, 4.83 Hz, 1H), 6.83-

3,4-dimethyl- (CAS 5973-71-7) 6.94 (m, 2 H), 6.96 (dd, J = 4.69, 3.22Hz, 2 H), 7.00- 7.11 (m, 3 H), 7.35-7.45 (m, 1 H), 7.98 (s, 1 H), 8.16(dd, J = 7.62, 1.76 Hz, 1 H), 8.26 (dd, J = 4.69, 2.05 Hz, 1 H). 163-{5-[(E)-2-(3,4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)Dimethylphenyl)-1-(2- acid, 2- δ ppm 2.04 (s, 3 H), 2.14 (s, 3methoxyphenyl)vinyl]- methoxy- H), 2.95-3.07 (m, 3 H), 3.661,2,4-oxadiazol-3-yl}-N- (CAS 93-25-4) (s, 3 H), 6.69-6.76 (m, 1 H),methylpyridin-2-amine Benzaldehyde, 6.81-6.90 (m, 1 H), 6.95-

3,4-dimethyl- (CAS 5973-71-7) 7.10 (m, 4 H), 7.15-7.23 (m, 2 H),7.43-7.55 (m, 1 H), 7.99 (s, 1 H), 8.18 (dd, J = 7.62, 2.05 Hz, 1 H),8.26 (dd, J = 4.83, 1.90 Hz, 1 H). 17 3-{5-[(E)-2-(3,4- 1- ¹H NMR (300MHz, DMSO-d₆) Dimethylphenyl)-1-(1- Naphthalene- δ ppm 1.98 (d, J =12.89 Hz, 3 naphthyl)vinyl]-1,2,4- acetic acid H), 2.04-2.27 (m, 3 H),3.00 oxadiazol-3-yl}-N- (CAS 86-87-3) (br. s., 1 H), 6.49-6.74 (m, 1methylpyridin-2-amine Benzaldehyde, H), 6.76-6.96 (m, 2 H), 7.07

3,4-dimethyl- (CAS 5973-71-7) (br. s., 1 H), 7.27 (br. s., 1 H), 7.49(br. s., 2 H), 7.73 (d, J = 16.41 Hz, 1 H), 7.81-8.04 (m, 3 H),8.06-8.33 (m, 1 H). 18 3-{5-[(E)-1-(3- Benzeneacetic ¹H NMR (300 MHz,DMSO-d₆) Chlorophenyl)-2-(4- acid, 3-chloro- δ ppm 2.25 (s, 3 H), 3.01(d, methylphenyl)vinyl]- (CAS 1878-65-5) J = 4.40 Hz, 3 H), 6.71 (dd,1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, J = 7.03, 4.98 Hz, 1 H), 7.09 (s,methylpyridin-2-amine 4-methyl- 5 H), 7.32-7.42 (m, 1 H),

(CAS 104-87-0) 7.52 (d, J = 4.98 Hz, 2 H), 8.07 (s, 1 H), 8.15 (d, J =7.62 Hz, 1 H), 8.26 (d, J = 2.93 Hz, 1 H). 19 3-{5-[(E)-1-(3-Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆) Chlorophenyl)-2-(3- acid,3-chloro- δ ppm 2.14 (s, 3 H), 2.99 (d, methylphenyl)vinyl]- (CAS1878-65-5) J = 4.69 Hz, 3 H), 6.66 (dd, 1,2,4-oxadiazol-3-yl}-N-Benzaldehyde, J = 7.62, 4.69 Hz, 1 H), 6.84- methylpyridin-2-amine3-methyl 6.92 (m, 1 H), 6.99 (s, 1 H),

(CAS 620-23-5) 7.01-7.06 (m, 1 H), 7.10 (d, J = 5.27 Hz, 2 H), 7.30 (dt,J = 7.33, 1.47 Hz, 1 H), 7.46 (dd, J = 4.10, 2.64 Hz, 1 H), 7.49-7.53(m, 1 H), 7.99 (s, 1 H), 8.11 (dd, J = 7.62, 2.05 Hz, 1 H), 8.24 (dd, J= 4.83, 1.90 Hz, 1 H). 20 3-{5-[(E)-1-(3- Benzeneacetic ¹H NMR (300 MHz,DMSO-d₆) Chlorophenyl)-2-(2- acid, 3-chloro- δ ppm 2.37 (s, 3 H), 3.00(d, methylphenyl)vinyl]- (CAS 1878-65-5) J = 4.69 Hz, 3 H), 6.67 (dd,1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, J = 7.62, 4.69 Hz, 1 H), 6.79 (s,methylpyridin-2-amine 2-methyl- 1 H), 6.87-6.97 (m, 2 H),

(CAS 529-20-4) 7.01-7.09 (m, 1 H), 7.22 (dd, J = 7.33, 1.47 Hz, 2 H),7.36 (d, J = 7.33 Hz, 1 H), 7.41 (dt, J = 3.00, 1.58 Hz, 2 H), 7.46 (s,1 H), 8.13-8.20 (m, 1 H), 8.25 (dd, J = 4.69, 2.05 Hz, 1 H). 213-{5-[(E)-1-(4- Benzeneacetic ¹H NMR (300 MHz, DMSO-d₆)Chlorophenyl)-2-(3,4- acid, 4-chloro δ ppm 2.08 (s, 3 H), 2.15 (s, 3dimethylphenyl)vinyl]- (CAS 1878-66-6) H), 3.01 (d, J = 4.10 Hz, 3 H),1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 6.70 (dd, J = 6.45, 4.98 Hz, 1methylpyridin-2-amine 3,4-dimethyl- H), 6.83 (d, J = 8.20 Hz, 1 H),

(CAS 5973-71-7) 7.02 (br. s., 3 H), 7.40 (d, J = 8.20 Hz, 2 H), 7.55 (d,J = 7.91 Hz, 2 H), 8.01 (s, 1 H), 8.14 (d, J = 7.33 Hz, 1 H), 8.26 (d, J= 3.22 Hz, 1 H). 22 3-{5-[(E)-1-(2- Benzeneacetic ¹H NMR (300 MHz,DMSO-d₆) Chlorophenyl)-2-(3,4- acid, 2-chloro δ ppm 2.05 (s, 3 H), 2.15(s, 3 dimethylphenyl)vinyl]- (CAS 2444-36-2) H), 3.00 (d, J = 4.69 Hz, 3H), 1,2,4-oxadiazol-3-yl}-N- Benzaldehyde, 6.71 (dd, J = 7.47, 4.83 Hz,1 methylpyridin-2-amine 3,4-dimethyl- H), 6.82 (d, J = 9.08 Hz, 1 H),

(CAS 5973-71-7) 6.92-6.98 (m, 1 H), 6.98- 7.10 (m, 2 H), 7.41-7.50 (m, 2H), 7.56 (td, J = 7.40, 2.20 Hz, 1 H), 7.64-7.72 (m, 1 H), 8.08-8.19 (m,2 H), 8.27 (dd, J = 4.69, 1.47 Hz, 1 H).

Biological Data

Compounds were synthesized and tested for S1P4 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P4 receptor in cells stablyexpressing the S1P4 receptor.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nMGTP γ³⁵S, and 5 μg membrane protein in a volume of 150 μl. Testcompounds were included in the concentration range from 0.08 to 5,000 nMunless indicated otherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P in the presence of test antagonist at concentrationsranging from 0.08 to 5000 nM.

Table 2 shows activity potency: S1P4 receptor from GTP γ³⁵S: nM, (EC₅₀).

Activity potency: S1P4 receptor from GTP γ³⁵S: nM, (EC₅₀),

TABLE 2 S1P4 IUPAC name EC₅₀ (nM)3-{5-[(Z)-2-(3,4-dimethylphenyl)-1-(2-thienyl)vinyl]-1,2,4- 140oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-1-(3-chlorophenyl)-2-(2-methylphenyl)vinyl]- 20021,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl) 550vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(2-methoxyphenyl) 501vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(3-methoxyphenyl) 1782vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(3-methylphenyl)vinyl]- 20201,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)vinyl]- 3751,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]- 79.291,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(3-thienyl)vinyl]-1,2,4- 665oxadiazol-3-yl}-N-methylpyridin-2-amineN-methyl-3-{5-[(Z)-2-(4-methylphenyl)-1-(2-thienyl)vinyl]- 6351,2,4-oxadiazol-3-yl}pyridin-2-amine

1. A compound having Formula I, or an enantiomer or tautomer therof, ora pharmaceutically acceptable salt thereof,

wherein: A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈cycloalkenyl; B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈cycloalkenyl; R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹,NO₂, NR¹²R¹³ or hydroxyl; R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl,CN, C(O)R¹¹, NO₂, NR¹²R¹³ or hydroxyl; R³ is H, halogen, —OC₁₋₈ alkyl,C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ or hydroxyl; R⁴ is H, halogen,—OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁵ is H,halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁶is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl; R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁸ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN,C(O)R¹¹, NR¹²R¹³ or hydroxyl; R¹¹ is H or C₁₋₈ alkyl; R¹² is H or C₁₋₈alkyl; R¹³ is H or C₁₋₈ alkyl; R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl;and R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.
 2. A compound according toclaim 1 wherein: A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈cycloalkenyl; and B is C₆₋₁₀ aryl.
 3. A compound according to claim 1wherein:


4. A compound according to claim 1 wherein:


5. A compound according to claim 1 wherein:


6. A compound according to claim 1 wherein:

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂; R² is H, halogen,—OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂; R³ is H, halogen, —OC₁₋₆ alkyl,C₁₋₆ alkyl, CN or NO₂; R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN orNO₂; R⁵ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂; R⁶ is H,halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN or NO₂; R⁷ is H, halogen, —OC₁₋₆alkyl, C₁₋₆₃ alkyl, CN or NO₂; R⁸ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆alkyl, CN or NO₂; R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and R¹⁵ is H,C₁₋₆ alkyl or C₃₋₆ cycloalkyl.
 7. A compound according to claim 6wherein: R⁴ is H, halogen or C₁₋₆ alkyl; R⁵ is H, halogen or C₁₋₆ alkyl;R⁶ is H, halogen or C₁₋₆ alkyl; R⁷ is H, halogen or C₁₋₆ alkyl; and R⁸is H, halogen or C₁₋₆ alkyl.
 8. A compound according to claim 7 wherein:R⁷ is H; and R⁸ is H.
 9. A compound according to claim 1 selected from:3-{5-[(E)-2-(3,4-dimethoxyphenyl)-1-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(4-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-Nmethylpyridin-2-amine;3-{5-[(E)-2-(3,4-dichlorophenyl)-1-phenylvinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-fluorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(Z)-2-(3,4-dimethylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;N-Methyl-3-{5-[(Z)-2-(4-methylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}pyridin-2-amine;3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-(trifluoromethyl)phenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;3-[(E)-2-(3,4-Dimethylphenyl)-1-{3-[2-(methylamino)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}vinyl]benzonitrile;3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-nitrophenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;3-{5-[(E)-1-(3,5-Difluorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(2-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(1-naphthyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(2-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(4-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(2-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine.10. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable adjuvant, diluents or carrier.
 11. Apharmaceutical composition according to claim 10 wherein the compound isselected from:3-{5-[(E)-2-(3,4-dimethoxyphenyl)-1-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-dimethylphenyl)-1-(4-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-dichlorophenyl)-1-phenylvinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-fluorophenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(Z)-2-(3,4-dimethylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;N-Methyl-3-{5-[(Z)-2-(4-methylphenyl)-1-(2-thienyl)vinyl]-1,2,4-oxadiazol-3-yl}pyridin-2-amine;3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-(trifluoromethyl)phenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;3-[(E)-2-(3,4-Dimethylphenyl)-1-{3-[2-(methylamino)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}vinyl]benzonitrile;3-(5-{(E)-2-(3,4-Dimethylphenyl)-1-[3-nitrophenyl]vinyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;3-{5-[(E)-1-(3,5-Difluorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(3-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(2-methoxyphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-2-(3,4-Dimethylphenyl)-1-(1-naphthyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(4-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(3-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(3-Chlorophenyl)-2-(2-methylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(4-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[(E)-1-(2-Chlorophenyl)-2-(3,4-dimethylphenyl)vinyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine.